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Isotype switching converts anti-CD40 antagonism to agonism to elicit potent antitumor activity

DOI: 10.1016/j.ccell.2020.04.013 DOI Help

Authors: Xiaojie Yu (University of Southampton) , H.t. Claude Chan (University of Southampton) , Hayden Fisher (University of Southampton) , Christine A. Penfold (University of Southampton) , Jinny Kim (University of Southampton) , Tatyana Inzhelevskaya (University of Southampton) , C. Ian Mockridge (University of Southampton) , Ruth R. French (University of Southampton) , Patrick J. Duriez (University of Southampton) , Leon R. Douglas (University of Southampton) , Vikki English (University of Southampton Faculty of Medicine, Southampton) , J. Sjef Verbeek (Leiden University Medical Centre) , Ann L. White (University of Southampton Faculty of Medicine) , Ivo Tews (University of Southampton) , Martin J. Glennie (University of Southampton Faculty of Medicine) , Mark S. Cragg (University of Southampton Faculty of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cancer Cell

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 21035

Open Access Open Access

Abstract: Anti-CD40 monoclonal antibodies (mAbs) comprise agonists and antagonists, which display promising therapeutic activities in cancer and autoimmunity, respectively. We previously showed that epitope and isotype interact to deliver optimal agonistic anti-CD40 mAbs. The impact of Fc engineering on antagonists, however, remains largely unexplored. Here, we show that clinically relevant antagonists used for treating autoimmune conditions can be converted into potent FcγR-independent agonists with remarkable antitumor activity by isotype switching to hIgG2. One antagonist is converted to a super-agonist with greater potency than previously reported highly agonistic anti-CD40 mAbs. Such conversion is dependent on the unique disulfide bonding properties of the hIgG2 hinge. This investigation highlights the transformative capacity of the hIgG2 isotype for converting antagonists to agonists to treat cancer.

Journal Keywords: antibody; CD40; antagonists; structure function; hIgG2; immunotherapy; agonists; immunostimulatory; Fc engineering; TNF receptor

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Medicine

Instruments: B21-High Throughput SAXS

Added On: 27/05/2020 10:26


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)